Acidyl derivative of unsymmetrical acetonalkamins and process of making same.



UNITED STATES PATENT OFFICE.

CARL I-I'ARRIES, OF BERLIN, GERMANY, ASSIGNOR TO GHEMISCHE FABRIK AUF AOTIEN, VORM. E. SCHERING, OF BERLIN, GERMANY.

ACIDYL DERIVATIVE OF UNSYMMETRICAL ACETONAI KAMINS AND PROCESS OF MAKING SAME.

SPECIFICATIGN formingpart of Letters Patent No. 692,656, dated February 4, 1902.

Application filecl December 11. 1897, Serial No. 661,513. (No specimens.) I

o o I o o 0H oH orr w/\ on I I l Valerylcliacetonamin.

o o on oH 'Vinyldiacetonamin.

Benzylidenediacetonamin.

as well as generally the analogously-consti- H I 011 0 o I NH in which R is meant for an aliphatic or arc- The present invention relates to the pro duction of acidyl derivatives from stable modifications of the unsymmetrical cyclical acetonalkamins,which acidyl derivatives possymmetrical bases of the triacetonamin scries-as, for example, vinyldiacetonamin,val-

eryldiacctonamin,oenanthdiacetonamin,benzylidenediacetonamin,piperonylenediacetonamin H onnc o 3 2 on,.omoa on on on Oenanthdiacetonamin.

Piperonylenediacetonamin.

matic radical. The isomeryof the said unsym metrical alkamins is a stereo-isomery similar to that of tropin and pseudo-tropin, and

therefore the true structure cannot be exexamples more clearly explain this:

( [1)Producii0n and Separation of theIsomer L'c Unsymmetrzcal Acetonallcmmn Buses.

1. Isomericoing Zdiacetonczlkanrins-(a) In acid s0Zut t'on.-Fifty grams of vinyldiacetonamin are dissolved in five hundred grams of water and gradually mixed with one kilogram of sodium amalgam. The reduction liquor is kept slightly acid by addition of dilute sulfuric acid, and is kept also at a temperature of about 35 to 40 centigrade. When all has been added, it is made alkaline and the product of reduction extracted with about one kilogram of warm ether, if necessary, under pressure. The ether is afterward distilled off to one-half and the solution then left to crystallize. Needles then crystallize out, which, crystallized out of benzene, melt at 161 to 162 centigrade. This body, hitherto unknown, represents the unstable form of vinyldiacetonalkamin. In the ethereal filtrate there is found a body which after crystallizing out of benzene melts at about 121 to 122 centigrade. It is identical with the vinyldiacetonalkamin obtained by Fischer (see Berz'chte derDeutschen Cheim'schen Gesellschctf, XVII, page 1794) and appears to be a uniform combination of the unstable vinyldiacetonalkamin, melting at 161 to 162, and the true stable vinyldiacetonalkamin, which melts at 138 and which is produced, according to the specification of Georg Merling and Albrecht Schmidt, Serial No. 607,110, filed September 26, 1896, by crystallizing the hydrochloricacid salt of the said Fischers base.

(1)) Reduction 'in neutral solution-Fifty grams of vinyldiacetonamin are dissolved in one kilogram of ether and reduced with two hundred and fiftygrams of aluminium amalgam without cooling, a little water being gradually added. After completion of the reduction it is filtered and the bases are separated by crystallization, as stated before.

2. Isomerz'c valeryldiacetonalkamins.--Example: Fifty grams valeryldiacetonamin are dissolved in fifty grams of water and grad nally mixed with about one kilogram of two and one-half per cent. sodium amalgam. The reduction liquor is constantly kept slightly acid by addition of dilute sulfuric acid and its temperature at about 35 to 40. The product of the reduction is made alkaline, shaken with ether, and the ethereal solution dried with potash and evaporated. The separation of the bases is here preferably performed by crystallization out of petroleum ether. To the residuum is added twice its Weight of petroleum ether and is kept cool. After some time the unstable valeryldiacetonalkamin crystallizes out, which after repeated recrystallizations melts at 93 to 9e centigrade. The stable modification of the alkamin is contained in the filtrate and has in a pure state a melting-point of 80 to 82 cent-igrade.

Isome'ricbenzylidenediacezfonalkcmti'na- By reducing benzylidenediacetonamin in the manner above described two isomeric benzylidenediacetonalkamins are also obtained. On long standing, after reduction is complete, a salt separates out. If this be mixed with caustic-soda solution a base is obtained which after recrystallization out of petroleum ether melts at about 68 and must be looked upon as the unstable modification. In the filtrate of the difficultly-soluble salt there is found the salt of an oily base which has hitherto not been obtained in a crystalline form.

4. lsomeric piperonylenecl'iaceionallcamins.lf piperonylenediacetonamin be reduced in the manner above described, an alkamin is obtained by crystallization out of petroleum ether, which represent-s the unstable form and possesses a melting-point of 108 to 109 Centigrade. "he stable modification is found in the filtrate as an oily body.

5. Isomeric 0enanthdiacetonallcami'ns.In the same way the production and separation of the two isomeric oenanthdiacetonalkamins are brought about. The unstable modification melts atabout 77 to 79centigrade. The stable form is an oily body.

The isomeric unsymmetrical acetonalkamin bases can further be produced in the manner as stated in the specification of Georg Merling and Albrecht Schmidt, Serial No. 607,110, for the two vinyldiacetonalkaminsthat is to say, by crystallizing a salt of the mixture of acetonalka mins obtained by the reduction of the corresponding acetonamin bases.

(B) Transformation of the Unstable Acetonctlkotmins into the Stable llfod'ifications by llfeans of Alkylates.

Example VL'ng Zdiacetonallcamin. The transformation may be brought about with, for instance, sodium amylate in a similar way to that given by lVillstttter for the transformation of tropin into pseudo-tropin. Two hundred grams of amyl alcohol and twenty grams of sodium are added to twenty grams of vinyldiacetonalkamin, melting at 161 to 162 centigrade, and boiled for about twenty hours. After mixing the product of reaction with dilute hydrochloric acid and shaking the hydrochloric-acid solution with other an isomeric vinyldiacetonalkamin is precipitated out of the solution by means of potash. The isomeric vinyldiacetonalkamin melts after recrystallizing out of benzene at 1 38 centigrade. In the same way from the body melting at 121 to 122 centigrade (Fischers base) a base melting at 138 centigrade is obtained by treating with sodium amylate. This base is identical with the base obtained from the vinyldiacetonalkamin melting at 161 to 162.

The stable forms of the alka'mins mentioned under 2, 3, 1, and 5 may also be produced in the manner described for the stable vinyldiacetonalkamin-viz by treating the corresponding unstable modification or the mix- IIO ture of both alkamins obtained by the reduction of acetonam'in bases with sodiumjam ylate.

(0) Production ofAc'idyl Drivativesfrom the Stable Modifications of the Unsymmeirt'cal Acetonalkamins.

Valuable alkaloids can be obtained if the hydrogen atom of thehydroxyl in the stable unsymmetrical acetoualkamins (in which for the present also their n-alkyl derivatives are included) is replaced by an acidyl group-as,

for instance, the benzoyl group, (O H.,CO,)

tives are desired by treating the said alkamin base with a watery solution of formaldehyde on a water-bath for about ten hours. The

"composition of the so-formed acidyl compounds answers the chemical formula:

oH-om I CH2\//CH2 in which formula R signifies an acidyl group, R an aliphatic or aromatic radical, and 11* a hydrogen atom which can be replaced by an alkyl group.

The bases expressed by the before-mentioned formula are insoluble in water and decompose upon boiling with watery or alcoholic alkali into the respective stable alkamin base (non-alkylated or alkylated) and into a salt of that acid the radical of which has been substituted for the hydrogen atom of the hydroxyl. The bases combine with inorganic and organic acids, thus forming the correspondi'ng salts,which possess anesthetic properties.

The acidyl derivatives from the stable vinyli diacetonal'ka-min, melting at138 centigrade, are described in "thespecification of Georg Merling and Albrecht Schmidt, Serial No. 607,110, filed September 26, 1896. In a similar Way to the acidyl derivatives from the vinyldiacetonalkamin, melting at 138, the acidyl derivatives from the other an alogouslyconstituted unsymmetricalacetonalkamins of the stable modifications are obtained.

Example-Benzoyl dert'oattiiefrom the stable vaZeryZdt'acetonaZka'mi-n.,The ethereal so lution of the stable valeryldiacetonalkamin,

which melts at 80 to 82 centigrade, is trans formed into its hydrochloric-acid salt, and the salt, dried at 100centigrad'e, is heated with benzoyl chlorid to about 130 centigrade. The melt is then dissolved in much water and shaken with ether to eliminate the unaltered benzoyl chlorid. The watery liquor is then made alkaline and shaken with ether. The oil remaining behind crystallizes out-of petroleum ether in shining. needles, which melt at to 66 centigrade. The hydrochloric acid salt is fairly difficultly soluble in water and crystallizes therefrom in compact crystals shining like glass. from the stable oenanthdiacetonalkamin obtained in the same manner represents a yellow oil. The hydrochloric acid difficultly dissolves in water and crystallizes therefrom in glossy hygroscopic crystals. The benzoyl derivative from the stable benzylidenediacetonalkamin is likewise'an oil. The benzoyl derivatives may, of-course, also be produced by using benzoic anhydrid in place ofbenzoyl chlorid or by starting with the free bases instead of using the hydrochlorates. The toluyl, phenylacetyl, and cinnamyl derivatives are obtained inan analogous manner. The toluyl-benzylidenediacetonalkamin is an oil gradually solidifying. It melts at about 78 to 80 centigrade. The toluyl'derivatives from the stable valeryl and oenanth diac'etonalkamin represent oils. The hydro chlorates are hygroscopic. benzylidenediacetonalkamin melts at from 118 to 119 centigrade. The-corresponding derivatives from the valeryldiacetomoenanthdiaceton, and piperonylenediaceton alkamin are oily bodies.

wise oily bodies. The alkylated acidyl derivatives from the stable unsymmetrical acetonalkamins also represent oils.

I'wish" it to be understood that I do no The benzoyl derivative The cinnamyl The phenylacetyl derivativesfrom the stable acetonalkamins are likeclaim under this application the acidyl compounds ofthe vinyldiacetonalkamin melting at 138 centigrade and of its alkyl deriva-' tives as new products or the method of pro-' duction of such acidylderivatives from the vinyldiacetonalkamin melting at 138, which form the object of the application of Georg Merling and Albrecht Schmidtflserial No.

607,110, filedSeptember 26, 1896, but that 1 (orI, ,o o

. i in which R signifies an acidyl group, R an aliphatic or aromatic radical and H* a hydro-- gen atom which'can be replaced by an alkyl group; such compounds in the form of free bases are oily bodies, insoluble in; water," decompose. upon boiling with watery 0r alcoholic alkali into therespective alkamin base I and a salt of that acid, the radical of which was substituted for the hydrogen atom of the hydroxyl acids and combines with inorganic and organic acids to form the corresponding salts which have anesthetic properties.

2. The process of obtaining local anesthetice from the stable modifications of the unsymmetrical cyclical acetonalkamins, which consists in treating the unsymmetrical bases of the triacetonamin series with a suitable reducing agent, then heating the product thus obtained with an alkylate, thus producing the stable modifications of the unsymmetrical bases of the triacetonalkamins, and then substituting in these bases an acid yl group for the hydrogen atom of the hydroxyl, by treating them with an acidyl reagent preferably after transforming them into a salt, substantially as described.

3. In the process of obtaining local anesagents.

In testimony whereof I have hereunto set my hand this 26th day of November, 1897.

CARL HARRIES.

Vitncsses HENRY IIASPER, WOLDEMAR I-IAUPT. 

